Abstract
BackgroundSeveral lines of evidence indicate that Sirt1, a class III histone deacetylase (HDAC) is implicated in the initiation and progression of malignancies and thus gained attraction as druggable target. Since data on the role of Sirt1 in pancreatic ductal adenocarcinoma (PDAC) are sparse, we investigated the expression profile and prognostic significance of Sirt1 in vivo as well as cellular effects of Sirt1 inhibition in vitro.MethodsSirt1 expression was analyzed by immunohistochemistry in a large cohort of PDACs and correlated with clinicopathological and survival data. Furthermore, we investigated the impact of overexpression and small molecule inhibition on Sirt1 in pancreatic cancer cell culture models including combinatorial treatment with chemotherapy and EGFR-inhibition. Cellular events were measured quantitatively in real time and corroborated by conventional readouts including FACS analysis and MTT assays.ResultsWe detected nuclear Sirt1 expression in 36 (27.9%) of 129 PDACs. SIRT1 expression was significantly higher in poorly differentiated carcinomas. Strong SIRT1 expression was a significant predictor of poor survival both in univariate (p = 0.002) and multivariate (HR 1.65, p = 0.045) analysis. Accordingly, overexpression of Sirt1 led to increased cell viability, while small molecule inhibition led to a growth arrest in pancreatic cancer cells and impaired cell survival. This effect was even more pronounced in combinatorial regimens with gefitinib, but not in combination with gemcitabine.ConclusionsSirt1 is an independent prognosticator in PDACs and plays an important role in pancreatic cancer cell growth, which can be levered out by small molecule inhibition. Our data warrant further studies on SIRT1 as a novel chemotherapeutic target in PDAC.
Highlights
Several lines of evidence indicate that Sirt1, a class III histone deacetylase (HDAC) is implicated in the initiation and progression of malignancies and gained attraction as druggable target
Cell culture The human pancreatic cancer cell lines PANC-1 (#CRL1469) and MiaPaCa-2 (#CRL-1420) were obtained from the American Type Culture Collection (ATCC, Rockville, MD, USA) and cultured in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum and P/S
Sirt1 expression in pancreatic ductal adenocarcinoma (PDAC) The specificity of the antibody used for immunohistochemistry was corroborated by siRNA-mediated knockdown of Sirt1 in MiaPaCa-2 and PANC-1 cells and subsequent immunoblotting with the Sirt1 antibody
Summary
Several lines of evidence indicate that Sirt, a class III histone deacetylase (HDAC) is implicated in the initiation and progression of malignancies and gained attraction as druggable target. Since data on the role of Sirt in pancreatic ductal adenocarcinoma (PDAC) are sparse, we investigated the expression profile and prognostic significance of Sirt in vivo as well as cellular effects of Sirt inhibition in vitro. Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related deaths in the United States. While substantial progress has been made in the understanding of pancreatic cancer biology [1], therapeutic concepts still provide only modest benefit [2]. The main prognosticators for surgically resectable PDACs are location, tumor size, resection margin, nodal status, and histological grade. These risk factors have been proven to be clinically useful, their ability to reliably predict outcome is limited and mainly reflects tumor distribution rather than tumor biology [4].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
